Epidemiological studies report that women are more likely than men to be affected by depression and that depression occurs more frequently in early spring. The biological reasons for these increased incidences are highly debated. Because many inflammatory conditions such as certain bacterial and viral respiratory infections peak around the same period of time, we hypothesize that peripheral inflammation will induce cytokine expression in the brain, that this cytokine expression will induce depression and that this effect will be higher in females. This R21 application is part of a broader goal of developing an animal model of neuroimmune interactions to study the mechanisms that may be promoting the higher incidence of depression and anxiety in women and during early spring. The objective of the proposed studies is to determine in a rodent animal model the relationship between peripheral activation of the immune response, expression of inflammatory genes in the brain and the effects of gonadal hormones in the modulation of behavioral responses of depression and anxiety. Based on our preliminary studies, we hypothesize that first: peripheral activation of the immune response due to inflammation in the upper-respiratory tract will induce cytokine expression in the brain, second: that this cytokine expression will be more pronounced in females as compared to males due to the presence of gonadal hormones, and third that this cytokine expression will affect the behavior of rats as demonstrated by increasing immobility time in the forced swim test. Treated animals with gonadal hormones and untreated animals will be challenged with bacterial and viral products in the nasal cavities and their cytokine profile in the brain will be determined by real-time RT-PCR. Another group of animals under the same conditions will be evaluated in the forced swim test and open field activity and their cytokine expression in the brain will be also determined. Administration of intranasal anti-inflammatory agents after the immune challenge will be used to test if they prevent cytokine expression in the brain and behavioral responses of depression. The results of the experiments proposed in this R21 application are expected to provide important preliminary data about gender differences and regulatory effects of gonadal hormones on inflammatory gene expression in the brain after intranasal immune-challenge. In addition, it will provide information about the interaction between gonadal hormones and cytokines in the modulation of behavioral responses to depression and anxiety. This information is not currently available in the literature and is critical to the initiation of studies on the mechanisms by which environmental factors in coordination with hormonal status may affect mood disorders. This information may be useful to prevent and treat depression in women. [unreadable] [unreadable] [unreadable]